The PI3Kδ/γ inhibitor duvelisib and the BCL2 inhibitor venetoclax synergized in vivo and ex vivo

  • Major Finding: The PI3Kδ/γ inhibitor duvelisib and the BCL2 inhibitor venetoclax synergized in vivo and ex vivo.

  • Concept: The combination treatment increased median survival in mouse models of Richter Syndrome.

  • Impact: These findings support an ongoing phase I/II trial of duvelisib plus venetoclax in Richter Syndrome.

Up to 10% of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) experience disease progression to Richter Syndrome, an aggressive lymphoma with poor prognosis. Based on early results from a phase I trial in which patients with CLL or SLL were treated with the PI3Kδ/γ inhibitor duvelisib and the BCL2 inhibitor venetoclax, Iannello and colleagues conducted ex vivo and in vivo experiments to evaluate the potential utility of this combination in Richter Syndrome. A proof-of-concept analysis using 24 primary Richter Syndrome samples showed that the majority were positive for PI3Kδ/γ and BCL2, with all samples being positive for PI3Kδ and 85% being positive for PI3Kδγ and BCL2, findings echoed in experiments using patient-derived xenografts (PDX). Ex vivo, different PDX models exhibited varying sensitivity to duvelisib and venetoclax alone and in combination. Although most were sensitive to the drugs, one PDX that did not express PI3K or BCL2 predictably exhibited complete resistance; however, in PDXs that were sensitive to the drugs, duvelisib and venetoclax acted synergistically rather than additively. In vivo, tumors in mice injected with drug-responsive Richter Syndrome cells exhibited reductions in volume upon treatment with duvelisib or venetoclax compared with controls, and combination treatment with both drugs was even more effective. Further, duvelisib and venetoclax increased overall survival in mice engrafted with Richter Syndrome cells by a median of six days, and the combination treatment extended survival to an even greater degree, resulting in a median increase in overall survival of 13 days. Mechanistically, duvelisib-induced PI3K inhibition led to downstream GSK3β activation and consequent degradation of the proto-oncoprotein c-MYC via the ubiquitin–proteasome pathway, an effect that synergized with the promotion of apoptosis caused by venetoclax-induced BCL2 inhibition. Collectively, these findings suggest that duvelisib and venetoclax may act synergistically in Richter Syndrome, CLL, or SLL, an idea that is currently being tested in a phase I/II clinical trial.

Iannello A, Vitale N, Coma S, Arruga F, Chadburn A, Di Napoli A, et al. Synergistic efficacy of dual PI3K-d/g inhibitor duvelisib with Bcl2 inhibitor venetoclax in Richter's Syndrome PDX models. Blood 2021 Mar 30 [Epub ahead of print].

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